Methods and compositions comprising desmopressin in combination with a 5-alpha reductase inhibitor

ABSTRACT

The invention provides methods and compositions for use of desmopressin in combination with a 5-alpha reductase inhibitor. The methods and compositions are useful in the treatment of nocturia and other urinary frequency disorders.

FIELD OF THE INVENTION

The invention provides methods and compositions for use of desmopressinin combination with a 5-alpha reductase inhibitor. The methods andcompositions are useful in the treatment of nocturia and other urinaryfrequency disorders.

BACKGROUND

Nocturia and other urinary frequency disorders affect a significantportion of the human population. Patients with nocturia experienceinterruption in sleep due to the need to get up during the night tourinate. Patients suffering from overactive bladder often experienceurge incontinence, urgency of urination, and higher urinary frequency.Overactive bladder can be caused by uncontrolled contractions of thebundles of smooth muscle fibers forming the muscular coat of the urinarybladder (the detrusor muscle) during the filling phase of the bladderand is more prevalent in elderly adults.

Compositions and methods for treating nocturia and other urinaryfrequency disorders have been described. For example, U.S. Pat. Nos.7,579,321; 7,799,761; and 8,143,225 describe pharmaceutical compositionsand methods using a low dosage of desmopressin. U.S. patent applicationpublication US 2009/0042970 describes treating nocturia and otherurinary frequency disorders using, for example, transdermaladministration of desmopressin. Also, U.S. patent applicationpublication US 2012/0015880 describes treating nocturia and otherurinary frequency disorders using, for example, intranasaladministration of desmopressin.

One of the challenges in treating nocturia and other urinary frequencydisorders using desmopressin is achieving a therapeutic, but non-toxic,blood plasma concentration of desmopressin. Administering a dose ofdesmopressin that is too large can have severe side effects, such ashyponatremia potentially resulting in seizures or death of the patient.As such, the need exists for compositions and methods which haveimproved safety profiles and/or improved efficacy using a lower dosageof desmopressin. The present invention addresses this need and providesother related advantages.

SUMMARY

The invention provides methods and compositions for use of desmopressinin combination with a 5-alpha reductase inhibitor. This combinationtherapy provides benefits to human subjects, especially adult males,suffering from disorders associated with or featuring undesirablevoiding of the subjects' bladder or frequent urge to void. Such personsmay suffer from overproduction of urine, inadequate urine concentration,low urine osmolality, excessive frequency of urination (e.g., excessivefrequency of urination associated with central diabetes insipidus),adult primary nocturnal enuresis, nocturia, over-active bladder syndrome(OAB), urinary urgency and frequency during waking hours, incontinence,or unwanted production of urine resulting in urine leakage at rest or byexertion or stress. The desmopressin and 5-alpha reductase inhibitor areadministered to the subject such that both exert physiological activityduring an overlapping time period. Exemplary 5-alpha reductaseinhibitors include, for example, dutasteride, epristeride, finasteride,izonsteride, turosteride, AS-601811, FK143, TF-505, and pharmaceuticallyacceptable salts thereof. In certain embodiments, the method optionallyfurther comprises administering an alpha-adrenergic receptor antagonist.

Accordingly, one aspect of the invention provides a method of inhibitingthe urge to urinate in a human subject over an interval of about twohours to no more than about seven hours. The method comprisesadministering to a human subject in need thereof an effective amount ofdesmopressin and a 5-alpha reductase inhibitor so that both exertphysiological activity during an overlapping time period. The dosage ofdesmopressin and/or 5-alpha reductase inhibitor and/or the dosingregimen may be adjusted so that the method inhibits the urge to urinatein a human subject over an interval of about 4 hours to about 7 hours.The desmopressin is administered at a dosage such that the subject doesnot experience hyponatramia, a harmful condition in which the sodiumconcentration in the subject's plasma is too low, e.g., below about 135mmol/L. Hyponatremia is avoided provided the maximum dose ofdesmopressin in the blood is less than 10 pg/ml, preferably less than 5pg/ml, and most preferably less than 5 pg/ml, e.g., 2 or 3 pg/ml. Severehyponatremia can result in electrolyte abnormalities that can causecardiac arrhythmias, heart attack, seizures, and/or stroke. In certainembodiments, the method optionally further comprises administering analpha-adrenergic receptor antagonist, such that, for example, each ofdesmopressin, the 5-alpha reductase inhibitor, and the alpha-adrenergicreceptor exert physiological activity during an overlapping time period.

5α-Reductase inhibitors are a group of medications with antiandrogenicactivity, used in treatment of benign prostatic hyperplasia. These drugsdecrease the levels of available 5α-reductase, thus reducing theproducts of its enzymatic reaction, including those which converttestosterone to the more potent dihydrotestosterone, and act onprogesterone, androstenedione, epi-testosterone, cortisol, aldosterone,and deoxycorticosterone.

Another aspect of the invention provides a method of inducing anantidiuretic effect in a human subject. The method comprisesadministering to a human subject in need thereof an effective amount ofdesmopressin and a 5-alpha reductase inhibitor so that both exertphysiological activity during an overlapping time period.

Another aspect of the invention provides a pharmaceutical compositioncomprising desmopressin, a 5-alpha reductase inhibitor, and apharmaceutically acceptable carrier. In certain embodiments, thepharmaceutical composition is formulated for transmucosaladministration, e.g., buccal or nasal administration to a human subject.In other embodiments, the composition is formulated as a transdermal orintradermal patch. In other embodiments the 5-alpha reductase inhibitoris taken orally while the desmopressin is taken transmucosally, e.g.,sublingually or intranasally.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 is a graph of desmopressin blood concentration and variable fluxrate versus time illustrating a 7-hour operation of a device and method.

FIG. 2 is a graph of desmopressin blood concentration and constant fluxrate versus time illustrating a 7-hour operation of a device and methodaccording to an alternative embodiment.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides methods and compositions for use of desmopressinin combination with a 5-alpha reductase inhibitor. This combinationtherapy provides benefits to subjects suffering from disordersassociated with or featuring undesirable voiding of the subjects'bladder of frequent urge to void. Such subjects may suffer fromoverproduction of urine, inadequate urine concentration, low urineosmolality, excessive frequency of urination (e.g., excessive frequencyof urination associated with central diabetes insipidus), adult primarynocturnal enuresis, nocturia, urinary urgency and frequency duringwaking hours, over-active bladder syndromes (OAB), incontinence, orunwanted production of urine resulting in urine leakage at rest or byexertion or stress. The desmopressin and 5-alpha reductase inhibitor areadministered to the subject such that both exert physiological activityduring an overlapping time period. The inhibitor may be administered atdoses below those used in current clinical practice, for the treatmentof Benign Prostate Hyperplasia (BPH). In certain embodiments, the methodoptionally further comprises administering an alpha-adrenergic receptorantagonist.

Various aspects of the invention are set forth below in sections;however, aspects of the invention described in one particular sectionare not to be limited to any particular section.

Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The terms “a,” “an” and “the” as used herein mean “one or more” andinclude the plural unless the context is inappropriate

As used herein, the term “effective amount” refers to the amount of acompound (e.g., a compound of the present invention) sufficient toeffect beneficial or desired results. An effective amount can beadministered in one or more administrations, applications or dosages andis not intended to be limited to a particular formulation oradministration route. As used herein, the term “treating” includes anyeffect, e.g., lessening, reducing, modulating, ameliorating oreliminating, that results in the improvement of the condition, disease,disorder, and the like, or ameliorating a symptom thereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for therapeutic use in vivo or exvivo.

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metals (e.g.,sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na⁺, NH₄ ⁺, and NW₄⁺ (wherein W is a C₁₋₄ alkyl group), and the like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

The terms “subject” and “patient” are used interchangeably and refer tohumans, especially adult male humans.

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

I. Therapeutic Methods

The invention provides therapeutic methods using desmopressin incombination with a 5-alpha reductase inhibitor. This combination therapyprovides benefits to subjects suffering from disorders associated withor featuring undesirable frequent urges to void the subjects' bladder.As described above, such subjects may suffer from overproduction ofurine, inadequate urine concentration, low urine osmolality, OAB,excessive frequency of urination (e.g., excessive frequency of urinationassociated with central diabetes insipidus), adult primary nocturnalenuresis, nocturia, urinary urgency and frequency during waking hours,incontinence, or unwanted production of urine resulting in urine leakageat rest or by exertion or stress. The desmopressin and 5-alpha reductaseinhibitor are administered to the subject such that both exertphysiological activity during an overlapping time period. Desirably,administration of desmopressin and the 5-alpha reductase inhibitorresults in a synergistic effect. Exemplary benefits from such asynergistic effect include improved reduction in a subject's urge tourinate and/or a reduction in the amount of desmopressin needed toachieve a therapeutic effect. Furthermore, administration of reducedamounts of the 5-alpha reductase inhibitor relative to the doses usedclinically to treat BPH mean that side effects of these drugs arereduced. In certain embodiments, the method optionally further comprisesadministering an alpha-adrenergic receptor antagonist.

One aspect of the invention provides a method of inhibiting the urge tourinate in a human subject over an interval of about two hours to nomore than about eight hours. The method comprises administering to ahuman subject in need thereof an effective amount of desmopressin and a5-alpha reductase inhibitor so that both exert physiological activityduring an overlapping time period. The dosage of desmopressin and/or5-alpha reductase inhibitor and/or the dosing regimen may be adjusted sothat the method inhibits the urge to urinate in a human subject overcertain intervals. For instance, in certain embodiments, the methodinhibits the urge to urinate in a human subject for an interval of about4 hours to about 6 hours (or 7 hours). Various embodiments of the method(e.g., dosage and route of administration of desmopressin, the 5-alphareductase inhibitor, the target patient population, and exemplarybenefits of the combination therapy) are described in the sectionsbelow. Further, in certain embodiments, the method optionally furthercomprises administering an alpha-adrenergic receptor antagonist, suchthat, for example, each of desmopressin, the 5-alpha reductaseinhibitor, and the alpha-adrenergic receptor exert physiologicalactivity during an overlapping time period.

Another aspect of the invention provides a method of inducing anantidiuretic effect in a human subject. The method comprisesadministering to a human subject, e.g., an adult male, in need thereofan effective amount of desmopressin and a 5-alpha reductase inhibitor sothat both exert physiological activity during an overlapping timeperiod. The method can be further characterized according to theinterval over which an antidiuretic effect is provided. For instance, incertain embodiments, an antidiuretic effect is achieved over an intervalof about two hours to no more than about seven or eight hours. Incertain other embodiments, the antidiuretic effect is achieved over aninterval of about four hours to about six hours. Various embodiments ofthe method (e.g., dosage and route of administration of desmopressin,dosage and route of administration of the 5-alpha reductase inhibitor,patient population, and exemplary benefits of the combination therapy)are described in the sections below. Further, in certain embodiments,the method optionally further comprises administering analpha-adrenergic receptor antagonist.

Desmopressin

The term “desmopressin” refers to 1-desamino-8-D-arginine vasopressinand includes the free base form and pharmaceutically acceptable saltsand hydrates thereof. One exemplary salt form is an acetate salt.Desmopressin, 1-desamino-8-D-arginine vasopressin monoacetate, alsoknown as DDAVP, is described in, for example, U.S. Pat. No. 3,497,491,and is commercially available as a prescription medication sold, forexample, under the names DesmoMelt, Stimate, MINIRIN® and DESMOSPRAY®.Desmopressin as an active pharmaceutical ingredient also is availablecommercially for formulation into new drug dose forms and compositions.The dosage of desmopressin administered to a human subject can beselected based on the weight of the subject and the desired durationover which a therapeutic effect is desired. The dosage can becharacterized according to the blood plasma concentration ofdesmopressin achieved.

Accordingly, therapeutic methods described herein can be characterizedaccording to the blood plasma concentration of desmopressin achieved. Incertain embodiments, the administering achieves in the human subject ablood plasma concentration of desmopressin that does not exceed 15pg/mL. In certain embodiments, the administering achieves in the humansubject a blood plasma concentration of desmopressin that does notexceed 10 pg/mL. In certain other embodiments, the administeringachieves in the human subject a blood plasma concentration ofdesmopressin in the range of about 0.2 pg/mL to about 5 pg/mL. In yetother embodiments, the administering achieves in the human subject ablood plasma concentration of desmopressin in the range of about 0.5pg/mL to about 2.5 pg/mL. In yet other embodiments, the administeringachieves in the human subject a blood plasma concentration ofdesmopressin in the range of about 0.5 pg/mL to about 1.5 pg/mL.Generally, the amount of desmopressin that reaches the bloodstream fromadministration of a given specific dose form should not exceed 2 ng/kgof body weight, and can be as low as 0.5 ng/kg, 1.0 ng/kg, or 1.5 ng/kg

Desmopressin can be administered using traditional routes ofadministration. For example, in certain embodiments, desmopressin isadministered transdermally, intradermally, transmucosally, or evenpossibly orally, although the variability of the bioavailability of oraldoses is so great that consistent very low blood concentrations are hardor impossible to achieve reproducibly. In certain other embodiments,desmopressin is administered transdermally, intradermally, ortransmucosally. In yet other embodiments, desmopressin is administeredtransdermally. In still other embodiments, desmopressin is administeredintranasally.

When desmopressin is administered transdermally or intradermally, themethod can be characterized according to the rate at which desmopressinis passed through the skin of a human subject. For example, in certainembodiments, desmopressin is administered at a first flux ratesufficient to achieve rapidly a desired blood plasma concentration ofdesmopressin, e.g., less than five, preferably less than 2 pg/ml, andthen at a second, lower flux rate sufficient to maintain the firstattained blood plasma concentration for a desired interval, e.g., sixhours. In certain embodiments, the method is further characterized by aflux range, such as where desmopressin is administered at a flux rateranging from about 5 ng/hour to about 35 ng/hour. In yet otherembodiments, desmopressin is administered at a flux rate ranging fromabout 5 ng/hour to about 35 ng/hour. In still other embodiments,desmopressin is administered at a flux rate ranging from about 5 ng/hourto about 15 ng/hour.

Various devices and methods for administering desmopressin have beendescribed previously and are contemplated for use in the presentinvention. See, for example, U.S. Patent Application Publication Nos. US2009/0042970 and US 2012/0015880, each of which are hereby incorporatedby reference. One device that may be used to administer desmopressin hasa depot containing a solution of desmopressin in a pharmaceuticallyacceptable carrier. An interface member for application to the skin of apatient, such as a permeable pad for attachment to the skin, or one oran array of microneedles, are in fluid communication with the depot. Thedevices comprise various means for delivering the desmopressin solutionfrom the depot to the interface member and downstream intradermally ortransdermally to the blood of a patient. The flux rate of thedesmopressin is controlled by setting the concentration of desmopressinin the depot, in combination with controlling either the rate of flow ofsolution from the depot, the rate of flow of solution to the interfacemember, the rate of flow of solution from the interface member into thebody of the patient, or by exploitation of some combination of thesecontrol points. In any event, the influx rate is controlled to besufficient to establish a desmopressin concentration in the blood of thepatient just above the water channel activation threshold, e.g., withinthe range of 0.1 to about 2.5 pg/ml, advantageously no greater than 1,1.5, 2, or 2.5 pg/ml. The flux rate in any case is insufficient toinduce a desmopressin concentration in the blood of the patient to alevel greater than about 10 pg/ml. The flux rate may be between about 5,10, 15, 20, 25, or 30 to 35 ng/hr (i.e., 5000, 10,000, 15,000, 20,000,25,000, or 30,000 to 35,000 pg/hr), advantageously about 10-20 ng/hr or20-35 ng/hr, more advantageously about 5-15 ng/hr, so as to establishthe desired blood concentration for a reasonable, predetermined timebefore the patient or the device shuts off desmopressin flow.

The dosage of desmopressin and/or duration of a therapeutic blood plasmaconcentration of desmopressin necessary to achieve a therapeutic effectis desirably less when desmopressin is used together with 5-alphareductase inhibitor than when desmopressin is administered alone, andthe urge to void is reduced as compared to when the 5-alpha reductaseinhibitor is administered alone. For example, in certain embodiments,the 5-alpha reductase inhibitor may reduce the urge to urinate for aperiod of time after which the desmopressin blood plasma concentrationdrops below the threshold necessary to achieve antidiuresis (activationof water channels in the kidney). As another example, the physiologicaleffect of the 5-alpha reductase inhibitor in combination with less urinefilling the bladder during the interval of induced antidiuresis togetherhave the effect of decreasing the patient's urge to urinate.

The flux rate of desmopressin may be preferably set so that, given thedesired blood concentration and the known clearance rate of desmopressin(half-life of about 1.5 to 2.0 hours), the patient reaches the desiredlow but supra-threshold blood concentration in a reasonable time, e.g.,less than an hour (and generally, the sooner, the better), and ismaintained within a low dose range just above the activation threshold(approximately within the range of 0.5 to 1.5 pg/ml) for a desired timeperiod (e.g., two hours for a workout, or 4-6 hours or 5-8 hours fortreatment of nocturia). Termination of the flux by automatic or manuallyactuated mechanisms built into the device, or by removal of the devicefrom contact with the skin, results in normal drug clearance mechanismsof the body of the patient rapidly reducing the low concentration to astill lower concentration, below the activation threshold.

The interface member of the device may comprise a desmopressinsolution-permeable membrane defining a surface for contact with the skinof the patient. The desmopressin solution-permeable surface permitsdelivery of the desmopressin from the depot through or to the skin ofthe patient. For highest bioavailability and precision of delivery,intradermal delivery is preferred. Intradermal delivery permits directdelivery to a vascularized compartment resulting in rapid absorptioninto the systemic circulation and correspondingly rapid on/off effects.While transdermal delivery is contemplated, its use is more subject tovariable bioavailability due to the stratum corneum functioning as aphysical barrier to drug reaching the epidermis, and to the creation ofa depot of drug in the epidermis.

Accordingly, transdermal delivery methods and devices can benefit fromtechniques that reduce the efficacy of the stratum corneum as a barrierto drug entry. These include, for example, mechanical methods forremoving portions of the stratum corneum before applying a transdermaldesmopressin delivery device. The skin can also be “micropunctured” tointroduce “micropassages” or “microfissures” across the stratum corneum,to enhance subsequent transdermal delivery, e.g. by one or moremicroneedles as described below.

The permeability of the stratum corneum can also be enhanced bytreatment with a chemical permeability enhancer, such asdimethylsulfoxide, decylmethylsulfoxide, diethylene glycol monomethylether, diethyleneglycol monoethyl ether, sodium laurate, sodium laurylsulfate, cetyltrimethylammonium bromide, benzalkonium chloride, lecithin(see, for example, U.S. Pat. No. 4,783,450, the teachings of which arehereby incorporated by reference), 1-n-dodecylazacycloheptan-2-one (see,for example, U.S. Pat. Nos. 3,989,816; 4,316,893; 4,405,616; and4,557,934, the teachings of which are hereby incorporated by reference),ethanol, propanol, octanol, benzyl alcohol, lauric acid, oleic acid,valeric acid, isopropyl myristate, isopropyl palmitate,methylpropionate, ethyl oleate, propylene glycol, ethylene glycol,glycerol, butanediol, polyethylene glycol, polyethylene glycolmonolaurate, urea, hydroxide (see, for example, U.S. Pat. No. 6,558,695,the teachings of which are hereby incorporated by reference),dimethylacetamide, dimethylformamide, 2-pyrrolidone,1-methyl-2-pyrrolidone, ethanolamine, diethanolamine, triethanolamine,salicylic acid, citric acid, succinic acid, and permeability enhancingpeptides (see, for example, U.S. Pat. No. 5,534,496, the teachings ofwhich are hereby incorporated by reference).

An efficient means of desmopressin delivery from the depot to the skinis intradermal administration, via an interface member comprising one ormore microneedles which penetrate the stratum corneum of the patient andenable fluid communication between the depot and the epidermis or directcontact with surfaces or cavities in the microneedles coated with orcontaining desmopressin. The length and size of the microneedles areadequate to penetrate the stratum corneum but small enough to producelittle if any sensation for the patient. For example, suitable lengthsare about 0.3 to 1.5 mm, advantageously between about 0.8 to 1.1 mm. Anexample of a single needle device is provided in U.S. Pat. No.6,939,324, the teachings of which are herein incorporated by reference.

A plurality of microneedles, e.g., in an array, may be desirable if moresurface area for delivery, or a more flexible patch, is desired. Themicroneedles may each have a channel that transports fluid from thedepot to the needle end, or the microneedles may otherwise allow forfluid delivery from the depot, e.g., with perforated or porous walls.Alternatively, the microneedles may be coated with a desmopressinpreparation or contain a film or matrix of desmopressin in cavities orin the material structure of the microneedle itself, to provide a burstof desmopressin upon application so as to aid rapid achievement of thethreshold activating concentration, optionally with desmopressinsolution passing through the needles to help achieve, or to maintain thedesired concentration.

The use of dissolvable microneedles is also contemplated, as their useavoids, in some cases, pain and/or irritation caused by metal needles orpiercing elements. U.S. Pat. No. 7,182,747, for example, discloses“solid solution perforators” which may be adapted for use in theinventions disclosed herein. In contrast to conventional hollow needletechnologies, these microneedles are made from a solid matrix ofdissolvable or biodegradable material that optionally holds one or moreselected drugs and is formed into one or more perforators.

Another device for delivering desmopressin is a patch that the userapplies before sleep, or before some other interval of activity wherethe patient desires to interrupt urine production. The patch may butneed not necessarily include an active solution flow control mechanism,e.g., with a user-selectable timing function, so the user can choose thelength of time he wishes to have normal urine production suppressed,i.e., in the case of sleep, roughly equivalent to or shorter than thedesired sleep time. The patient removes the patch from its packaging,sets the delivery time if necessary, and applies the patch to an area ofthe skin. Desmopressin delivery at the levels and rates described hereinthen begins, and urine production is suppressed for the desired time.When the flow controller is shut off, the patch is removed, or thedesmopressin depot is exhausted, normal urine production returnsquickly. In a preferred simple version of the device, the amount ofdesmopressin in the depot and its engineered flux rate throughexhaustion of the depot fixes the delivery time, e.g., five to sevenhours, with termination of flux corresponding simply to exhaustion ofthe patch delivery. Thus, the patient can sleep without having to wakeperhaps repeatedly during the sleep hours, or engage in other activitywithout concern about involuntary voiding.

Turning to the drawings, the operation of exemplary devices will bedescribed.

FIG. 1 illustrates operation of an exemplary embodiment of the inventionin treating a patient for whom shutting off urine production is desired,e.g., treating nocturia. A device according to the invention thatdelivers a low dosage/low variable flux of desmopressin to a patient isaffixed to the skin of the patient, the patient urinates, and the deviceis activated at 10:00 P.M. FIG. 1 shows illustrative and exemplary blooddesmopressin concentrations and the flux rates for this patient atvarious times following application or activation of the device. At onehour (11:00 P.M.), the desmopressin flux rate has peaked at about 20ng/hr and has raised the patient's blood desmopressin concentration toover about 1.0 pg/ml, i.e., above the concentration sufficient toactivate kidney water channels and to induce an antidiuretic effect(here illustrated as being at a blood concentration of about 0.8 pg/ml).At 2 hours (midnight), the flux rate is decreasing slightly but is stillin the 20 ng/hr range, and blood desmopressin concentration is elevatedto about 1.5 pg/ml. These values decrease slowly but are relativelyconstant for the next 2.5 to 3 hours. After about 5 hours (3:00 AM), theflux rate has decreased to a level where the activation concentration ofdesmopressin cannot be sustained. As the flux rate continues to drop,the blood desmopressin concentration falls below the water channelactivation level, and urine production commences (here at about 3:45AM). By 5:00 AM blood concentration is below about 0.5 pg/ml and fluxrate has dropped to zero. By 6:00 AM the patient is awake and feels anormal urge to void as urine has been produced for the last hour and ahalf or so of sleep. During the sleep there is a sustained antidiureticinterval, little or no urine production, and no bothersome orsleep-interrupting urge to void. The flux rate of desmopressin and theblood concentration of desmopressin may be more or less depending on thedosage of 5-alpha reductase inhibitor administered to the patient. It isappreciated that the desmopressin and 5-alpha reductase inhibitor may beadministered to the patient in separate formulations, or thedesmopressin and 5-alpha reductase inhibitor may be mixed together toform a single formulation that is administered to the patient.

FIG. 2 illustrates another exemplary embodiment of the invention fortreating a patient to shut off urine production, e.g., treatingnocturia. A device according to the invention that delivers a low dosageconstant flux of desmopressin is affixed to the skin of the patient. Thedevice is activated (if necessary) and the patient urinates at 10:00 PM.FIG. 2 shows illustrative and exemplary blood desmopressinconcentrations resulting from a flux of about 10 ng/hr over about a fivehour infusion from 10:00 PM to 3:00 AM relative to the threshold bloodconcentration for desmopressin's antidiuretic effect. Within about anhour from flux initiation the blood desmopressin concentration exceedsthe threshold level and begins to exert an antidiuretic effect. Theblood concentration approaches a more or less stable range within abouttwo to three hours (between about 1.0 and 1.5 pg/ml) which is sustainedduring the remainder of the five hour flux until 3:00 AM. At this timethe flux is discontinued (e.g., timed out or exhausted). Now the blooddesmopressin concentration decreases from clearance mechanisms inaccordance with the drug's elimination half-life, falling below thethreshold approximately two hours later (5:00 AM). By 7:00 AM thepatient has produced urine, and wakes to void. The flux rate ofdesmopressin and the blood concentration of desmopressin may be more orless depending on the dosage of 5-alpha reductase inhibitor administeredto the patient.

The foregoing examples are for illustrative purposes only. Theactivation concentration will of course vary among individuals, as willblood volume. The important principle in the operation of the device isthat the antidiuretic effect can be controlled safely, as the diureticaction is maintained by maintaining a low desmopressin concentration bya continuous low influx of the drug, and an interruption of the influxpermits the body to rapidly clear the drug and to re-establish normalurine production. This means that the patch devices enhance safety ofdesmopressin administration, with little or no risk of development ofwater intoxication when used as directed.

In accordance with the invention, the 5-alpha reductase inhibitor may bepresent in admixture with the desmopressin in the patch devicesdescribed above, or with the intranasal dose form disclosed below, butpreferably is supplied as a daily oral dose, and is active and presentin the blood plasma during the time the desmopressin is present.

An exemplary device for intranasal administration of desmopressin is asafety dispenser for inducing in members of a target patient populationan antidiuretic effect while reducing the risk that a member of thepopulation may develop hyponatremia. The dispenser comprises a reservoirhaving disposed therein a composition comprising a preparation ofdesmopressin and a nasal membrane permeation enhancer in an amountsufficient to constitute multiple drug doses. The reservoir is incommunication with an outlet and is fitted with a pump, preferably adisposable pump, and preferably one that can be actuated manually, suchas a squeeze bottle actuated dispenser, or a plunger pump fitted onto aglass bottle. The pump enables serially dispensing multiple metereddoses from the reservoir through the outlet in the form of a spray intoa nostril or nostrils of a patient so as to deposit a dose of consistentsize onto an intranasal mucosal or other surface.

Each spray comprises a multiplicity of droplets, preferably with anaverage volume distribution in the range of 20 μm for D10 to about 300μm for D90. This means that about 10% of the droplets are smaller thanabout 20 μm in diameter and 90% are smaller than 300 μm in diameter.Each spray dose is preferably of a weight and desmopressin concentrationsuch that it comprises between 0.5 ng desmopressin per kilogram of thepatient's body weight and 75 ng desmopressin per kilogram of thepatient's body weight. The spray is characterized by a desmopressinbioavailability greater than about 5%, that is, between about 5% and 25%of the active in the composition actually enters the patient'sbloodstream and contributes to the drug effect, and the remainder isdegraded, typically by digestion. Generally, the higher thebioavailability of a spray, the less desmopressin per spray needs to bedelivered into a nasal cavity, and vice versa, the goal being to achievemore consistently a target desmopressin maximum blood concentration(C_(max)) in members of the patient population.

The combination of properties of the spray dispenser and the compositionit contains enables respective doses of spray to be effective torestrict the concentration of desmopressin produced in the bloodstreamof patients, on a per kilogram basis, to a relatively narrow range,thereby to achieve a relatively consistent, time limited duration ofantidiuresis. Stated differently, respective successive spray dosesestablish in a patient by drug transport across intranasal mucosalmembranes a C_(max) of desmopressin which is relatively consistent. Theamount of drug delivered to the bloodstream for repeated doses from thesame dispenser to the same person preferably should differ no more than100%, and preferably less than 50%. The dispenser's coefficient ofvariation is similar to the coefficient of variation of C_(max) producedby serial subcutaneous doses of desmopressin designed to achieve thesame target C_(max). Preferably, respective successive spray doses aresufficient to establish in a patient by intranasal delivery a C_(max) ofdesmopressin having a coefficient of variation within about 50%, morepreferably about 25%, of the coefficient of variation of C_(max)produced by a subcutaneous dose of desmopressin designed to achieve thesame target C_(max).

The value of the target C_(max) may be varied, depending on the durationof the antidiuretic interval the dispensed composition is designed toinduce and the dosage of 5-alpha reductase inhibitor. For example, aproduct designed for a 7-8 hour interval of urine production suppressionmight be designed to deliver a C_(max) of no more than 15+/−3 pg/ml.Thus, by way of illustration, a 7 hour product might have abioavailability of 10% and a desmopressin load per spray of 0.75 μg or750 ng. This would mean that about 75 ng of drug would reach thepatient's bloodstream, and that a 70 kg (˜155 lb.) adult would receive adose in his bloodstream of about 1.0 ng/kg, and achieve a target C_(max)of less than about 5 pg/ml. Another embodiment of the same product mighthave a bioavailability of 8% and a desmopressin load per spray of 2.0 μgor 2000 ng, delivering about 160 ng drug to the patient's bloodstream asan effective dose of 160 ng/75 kg or slightly more than 2 ng/kg, and thetarget C_(max) of less than about 10 pg/ml. Another exemplary productmay be designed for a 3-4 hour urine interruption and might deliver aC_(max) of no more than about 3 pg/ml.

Alternatively, a single dispenser which delivers, e.g., 200 ng or 500 ngper spray, when used in accordance with package insert or physicianinstructions, may serve to achieve, for example, different durations ofantidiuresis in the same person or the same duration of antidiuresis inadults of different weight, simply by varying the number of spaysdelivered per administration event. Typically, about 20 minutes to anhour after administration of the pharmaceutical composition of thepresent invention, the mean urine output per minute in a treatedindividual decreases to less than about 4 ml/minute, preferably lessthan about 1 ml/min, and stays in this low range for a desired timeperiod, such as 180 minutes, 240 minutes, 300 minutes, 360 minutes, or420 minutes. About twenty minutes after administration, the mean urineosmolarity is greater than about 300 mOsmol/kg and remains at highconcentration for a period of time ranging up to 180 minutes, 240minutes, 300 minutes, 360 minutes, or 420 minutes.

One important property of the intranasal administration is that itconsistently deliver per spray a maximum blood concentration within arelatively narrow time and dose range, and therefore avoid or minimizeaccidental delivery of a larger dose resulting in a longer than expectedantidiuretic effect and the possibility of induction of hyponatremia.Consistent delivery, as the phrase is used herein, should be taken tomean repeatable within a range similar to the range observed whenadministering very low doses of desmopressin by subcutaneous injection,or perhaps somewhat greater. Such consistency generally is achieved moreeasily exploiting formulations with higher bioavailability, andaccordingly a bioavailability of at least 5%, preferably at least 10%,more preferably at least 15%, and preferably even higher is preferred.Higher bioavailability is achieved by exploiting formulation technology,especially the use of permeation enhancers, and by chemical engineeringof the spray composition as disclosed herein.

In one embodiment, the dispenser may further comprise means for blockingdispensing of a second desmopressin spray, or series of sprays above acertain dose, e.g., above about a dose sufficient to produce a bloodconcentration above about 10 to 12 pg/ml, for a predetermined timeinterval after dispensing a first dose. This can be achieved passivelyas a consequence of the design of the spray mechanism as disclosed, forexample, in U.S. Pat. No. 7,335,186, the disclosure of which isincorporated herein by reference. Alternatively, an active timer,powered by a battery, mechanical spring, or compressed gas within thedispenser, may be included together with mechanisms known per sedesigned to preclude a second dispensing until passage of apredetermined interval, e.g., 8 hours, or somewhere between 6 to 24hours. Such a mechanism can discourage abuse of the product and furtherminimize the chances that a patient may inadvertently or intentionallyself-induce antidiuresis for too long.

Exemplary permeation enhancers for use in the formulation are “Hsiehenhancers” (see U.S. Pat. No. 5,023,252) available commercially fromCPEX Pharmaceuticals (formerly Bentley) of Exeter, N.H. Preferred withinthe class of Hsieh enhancers useful in the articles of manufacture arethose disclosed in U.S. Pat. No. 7,112,561 and U.S. Pat. No. 7,112,561,and the currently most preferred are disclosed in U.S. Pat. No.7,244,703, such as cyclopentadecanolide, known in the trade as CPE-215.Many other enhancers may be used.

In some embodiments, the invention provides uses of the safety dispenserto induce an antidiuretic effect. The dispenser and desmopressinformulation may comprise any of the properties described herein. Forexample, in one embodiment, the desmopressin C_(max) is directlyproportional to the amount of nasally administered desmopressin over aC_(max) ranging from about 0.5 pg/ml to about 10.0 pg/ml. The value ofthe target C_(max) may be varied, depending on the duration of theantidiuretic interval the dispensed composition is designed to induceand the dosage of 5-alpha reductase inhibitor. For example, use of asafety dispenser described herein may produce antidiuresis for less thanabout 8 hours, less than about 6 hours, for between about 2 and 4 hours,or for between about 4 and 7 hours. Another exemplary use of a productmay be designed to deliver a C_(max) in a patient of no more than about15 pg/ml, 10 pg/ml, 7 pg/ml, or 3 pg/ml.

5-Alpha Reductase Inhibitors

5-Alpha reductase inhibitors are a class of medicinal agents thatinhibit the activity of 5-alpha reductase. Exemplary 5-alpha reductaseinhibitors include, for example, dutasteride, epristeride, finasteride,izonsteride, turosteride, AS-601811, FK143, TF-505, and pharmaceuticallyacceptable salts thereof. A brief description of potentially suitable5-alpha reductase inhibitors is provided below.

Dutasteride

Dutasteride has the chemical name (5α,17β)-N-{2,5bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide andis commercially available as a soft gelatin capsule under the trade nameAVODART®. A pharmaceutically acceptable salt of dutasteride may be used.Dutasteride may be administered via routes known in the art, such as byoral administration. The amount of dutasteride or pharmaceuticallyacceptable salt thereof administered to the patient can be in the rangeof, for example, about 0.1 mg to about 5 mg per day. In certainembodiments, dutasteride is administered (e.g., orally) at a dailydosage ranging from about 0.1 to about 1 mg, about 1 mg to about 2 mg,about 2 mg to about 3 mg, about 3 mg to about 4 mg, or about 4 mg toabout 5 mg. In certain other embodiments, dutasteride is administered(e.g., orally) at a daily dosage ranging from or about 0.3 mg to about0.7 mg. The currently preferred dose for an adult male is less than therecommended dose for treatment of BPH, namely, less than 0.5 mg/day,e.g., 0.1 to 0.3 or 0.4 mg/day.

Epristeride

Epristeride has the chemical name17β-(N-tert-butylcarboxamido)androsta-3,5-diene-3-carboxylic acid. Apharmaceutically acceptable salt of epristeride may be used. The amountof epristeride or pharmaceutically acceptable salt thereof administeredto the patient can be in the range of, for example, about 1 mg to about500 mg. In certain embodiments, epristeride is administered at a dailydosage ranging from about 0.1 mg to about 1 mg, about 1 mg to about 2mg, about 2 mg to about 5 mg, about 5 mg to about 10 mg, about 1 mg toabout 50 mg, about 50 to about 100 mg, about 100 mg to about 150 mg,about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mgto about 300 mg, about 300 mg to about 350 mg, about 350 mg to about 400mg, about 400 mg to about 450 mg, or about 450 mg to about 500 mg.

Finasteride

Finasteride has the chemical nameN-(1,1-dimethylethyl)-3-oxo-(5α,17β)-4-azaandrost-1-ene-17-carboxamideand is commercially available in tablet form under the trade namePROPECIA®. A pharmaceutically acceptable salt of finasteride may beused. Finasteride may be administered via routes known in the art, suchas by oral administration. The amount of finasteride or pharmaceuticallyacceptable salt thereof administered to the patient can be in the rangeof, for example, from about 0.2 mg to about 20 mg per day. In certainembodiments, finasteride is administered (e.g., orally) at a dailydosage ranging from about 0.2 mg to about 0.5 mg, about 0.5 mg to about1 mg, about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg toabout 5 mg. In certain other embodiments, finasteride is administered(e.g., orally) at a daily dosage ranging from about 1 mg to about 5 mg.The currently preferred dose of Finasteride for an adult male incombination with desmopressin is less than the recommended Finasteridedose for treatment of BPH, namely, less than 5 mg/day, e.g., about 1 to3 or 4 mg/day. Less than 1.0 mg/day often works well and avoids mostadverse side effects.

AS-601811

AS-601811 has the chemical name4,8-dimethyl-2,3,5,6-tetrahydro-1H-benzo[c]quinolizin-3-one. Apharmaceutically acceptable salt of AS-601811 may be used. The amount ofAS-601811 or pharmaceutically acceptable salt thereof administered tothe patient can be in the range of, for example, about 1 mg to about 500mg. In certain embodiments, AS-601811 is administered at a daily dosageranging from about 1 mg to about 50 mg, about 50 to about 100 mg, about100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg toabout 250 mg, about 250 mg to about 300 mg, about 300 mg to about 350mg, about 350 mg to about 400 mg, about 400 mg to about 450 mg, or about450 mg to about 500 mg.

Izonsteride

Izonsteride has the chemical name(4aR,10bR)-8-((4-ethyl-2-benzothiazolyl)thio)-1,4,4a,5,6,10b-hexahydro-4,10b-dimethylbenzo[f]quinolin-3-(2H)-one.A pharmaceutically acceptable salt of izonsteride may be used. Theamount of izonsteride or pharmaceutically acceptable salt thereofadministered to the patient can be in the range of, for example, about 1mg to about 500 mg. In certain embodiments, izonsteride is administeredat a daily dosage ranging from about 1 to about 50 mg, about 50 to about100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg,about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 300 mgto about 350 mg, about 350 mg to about 400 mg, about 400 mg to about 450mg, or about 450 mg to about 500 mg.

Turosteride

Turosteride has the chemical name1,3-diisopropyl-1-((4-methyl-3-oxo-4-aza-5alpha-androstan-17beta-yl)carbonyl)urea. A pharmaceutically acceptablesalt of turosteride may be used. The amount of turosteride orpharmaceutically acceptable salt thereof administered to the patient canbe in the range of, for example, about 1 mg to about 500 mg. In certainembodiments, turosteride is administered at a daily dosage ranging fromabout 1 mg to about 50 mg, about 50 to about 100 mg, about 100 mg toabout 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250mg, about 250 mg to about 300 mg, about 300 mg to about 350 mg, about350 mg to about 400 mg, about 400 mg to about 450 mg, or about 450 mg toabout 500 mg.

FK143

FK143 has the chemical name4-[3-[3-[bis(4-isobutylphenyl)methyl-amino]benzoyl]-1H-indol-1-yl]butyricacid. A pharmaceutically acceptable salt of FK143 may be used. Theamount of FK143 or pharmaceutically acceptable salt thereof administeredto the patient can be in the range of, for example, about 1 mg to about500 mg. In certain embodiments, FK143 is administered at a daily dosageranging from about 1 mg to about 50 mg, about 50 to about 100 mg, about100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg toabout 250 mg, about 250 mg to about 300 mg, about 300 mg to about 350mg, about 350 mg to about 400 mg, about 400 mg to about 450 mg, or about450 mg to about 500 mg.

TF-505

TF-505 has the chemical name(−)-(S)-4-[1-[4-[1-(4-isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyricacid. A pharmaceutically acceptable salt of TF-505 may be used. TF-505may be administered via routes known in the art, such as by oraladministration. The amount of TF-505 or pharmaceutically acceptable saltthereof administered to the patient can be in the range of, for example,from about 10 mg to 100 mg per day. In certain embodiments, TF-505 isadministered (e.g., orally) at a daily dosage ranging from about 1 mg toabout 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg,about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg toabout 60 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg,about 80 mg to about 90 mg, or about 90 mg to about 100 mg. In certainother embodiments, TF-505 is administered (e.g., orally) at a dailydosage ranging from about 25 mg to about 50 mg.

It is appreciated that more than one 5-alpha reductase inhibitor can beadministered to a subject. For example, in certain embodiments,dutasteride and a pharmaceutically acceptable salt of tamsulosin (e.g.,tamsulosin hydrochloride) are administered to the subject. Capsulescontaining dutasteride and tamsulosin hydrochloride are commerciallyavailable under the trademark JALYN®.

Further, it is appreciated that the 5-alpha reductase inhibitor may beadministered by traditional routes of administration known in the art.Certain routes of administration may be preferred for a particulartherapeutic agent, such as where a particular route of administrationreduces first-pass metabolism or has improved bioavailability. Incertain embodiments, the 5-alpha reductase inhibitor is administeredorally, transdermally, intradermally, or by transmucosal administrationalone or together in admixture with desmopressin. In yet otherembodiments, the 5-alpha reductase inhibitor is administered orally.

A preferred daily dose range of a 5-alpha reductase inhibitor is a dailydosage amount less than that used for monotherapy to treat BPH. Incertain embodiments, the combination therapy using desmopressin and the5-alpha reductase inhibitor uses a daily dosage amount of 5-alphareductase inhibitor that is about 40% to about 50%, about 50% to about60%, about 60% to about 70%, about 70% to about 80%, about 80% to about90%, or about 75% to about 90% of the daily dosage used in monotherapyto treat BPH.

The method may also be characterized according to the time periodbetween the start of administration of desmopressin and administrationof the 5-alpha reductase inhibitor. In certain embodiments, the firstadministration of desmopressin may coincide with administration of the5-alpha reductase inhibitor. Alternatively, the start of administrationof desmopressin may be before or after the start of administration ofthe 5-alpha reductase inhibitor. In certain embodiments, the 5-alphareductase inhibitor is administered within 1 hour of the start ofdesmopressin administration. In certain embodiments, the 5-alphareductase inhibitor is administered within 0.5 hours, 1 hour, 1.5 hours,or 2 hours of the start of desmopressin administration. In certainembodiments, the 5-alpha reductase inhibitor is administered in themorning (e.g., at a daily dosage sufficient to provide a therapeuticbenefit at least during the time period over which desmopressin isadministered).

Alpha-Adrenergic Receptor Antagonists

Alpha-adrenergic receptor antagonists are a class of medicinal agentsthat are antagonists of the alpha-adrenergic receptor. Alpha-adrenergicreceptor antagonists are sometimes referred to as alpha-blockers.Exemplary alpha-adrenergic receptor antagonists include alfuzosin,doxazosin, idazoxan, prazosin, silodosin, tamsulosin, terazosin,tolazoline, yohimbine, and pharmaceutically acceptable salts thereof. Abrief description of each of these potentially suitable alpha-adrenergicreceptor antagonists is provided below.

Alfuzosin

Alfuzosin has the chemical nameN-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide.A pharmaceutically acceptable salt of alfuzosin may be used. Forexample, the hydrochloride salt of alfuzosin is commercially availableunder the trademark UROXATRAL® in tablet form. Alfuzosin may beadministered via routes known in the art, such as by oraladministration. The amount of alfuzosin or a pharmaceutically acceptablesalt thereof administered to the patient can be in the range of, forexample, about 1 mg to about 100 mg per day. In certain embodiments,alfuzosin is administered (e.g., orally) at a daily dosage ranging fromabout 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg toabout 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg,about 40 mg to about 50 mg, about 50 mg to about 60 mg, about 60 mg toabout 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, orabout 90 mg to about 100 mg. In certain other embodiments, alfuzosin isadministered (e.g., orally) at a daily dosage ranging from about 7.5 mgto about 12.5 mg, about 9 mg to about 11 mg, or about 9.5 mg to about10.5 mg.

Doxazosin

Doxazosin has the chemical name1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxin-2-yl)carbonyl]piperazine.A pharmaceutically acceptable salt of doxazosin (e.g., doxazosinhydrochloride or doxazosin mesylate) may be used. For example, themesylate salt of doxazosin is commercially available under the trademarkCARDURA® in tablet form. Doxazosin may be administered via routes knownin the art, such as by oral administration. The amount of doxazosin or apharmaceutically acceptable salt thereof administered to the patient canbe in the range of, for example, about 0.1 mg to about 50 mg per day. Incertain embodiments, doxazosin is administered (e.g., orally) at a dailydosage ranging from about 0.1 mg to about 0.5 mg, about 0.5 mg to about1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mg to about 2.0 mg,about 2.0 mg to about 2.5 mg, about 2.5 mg to about 3.0 mg, about 3.0 mgto about 3.5 mg, about 3.5 mg to about 4.0 mg, about 4.0 mg to about 4.5mg, about 4.5 mg to about 5.0 mg, about 5.0 mg to about 5.5 mg, about5.5 mg to about 6.0 mg, about 6.0 mg to about 6.5 mg, about 6.5 mg toabout 7.0 mg, about 7.0 mg to about 7.5 mg, about 7.5 mg to about 8.0mg, about 8.0 mg to about 9.0 mg, about 9.0 mg to about 10 mg, about 10mg to about 12 mg, about 12 mg to about 14 mg, about 14 mg to about 16mg, about 16 mg to about 18 mg, about 18 mg to about 20 mg, about 20 mgto about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg,about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mgto about 50 mg.

Idazoxan

Idazoxan has the chemical name2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole. Apharmaceutically acceptable salt of idazoxan (e.g., idazoxanhydrochloride) may be used. Idazoxan may be administered via routesknown in the art, such as by oral administration. The amount of idazoxanor a pharmaceutically acceptable salt thereof administered to thepatient can be in the range of, for example, about 0.1 mg to about 100mg per day. In certain embodiments, idazoxan is administered (e.g.,orally) at a daily dosage ranging from about 0.1 mg to about 0.5 mg,about 0.5 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mgto about 2.0 mg, about 2.0 mg to about 2.5 mg, about 2.5 mg to about 3.0mg, about 3.0 mg to about 3.5 mg, about 3.5 mg to about 4.0 mg, about4.0 mg to about 4.5 mg, about 4.5 mg to about 5.0 mg, about 5.0 mg toabout 6.0 mg, about 6.0 mg to about 7.0 mg, about 7.0 mg to about 8.0mg, about 8.0 mg to about 9.0 mg, about 9.0 mg to about 10 mg, about 10mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mgto about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg,about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg toabout 80 mg, about 80 mg to about 90 mg, or about 90 mg to about 100 mg.

Prazosin

Prazosin has the chemical name1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine.A pharmaceutically acceptable salt of prazosin may be used. For example,the hydrochloride salt of prazosin is commercially available under thetrademark MINIPRESS® in capsule form. Prazosin may be administered viaroutes known in the art, such as by oral administration. The amount ofprazosin or a pharmaceutically acceptable salt thereof administered tothe patient can be in the range of, for example, about 0.1 mg to about100 mg per day. In certain embodiments, prazosin is administered (e.g.,orally) at a daily dosage ranging from about 0.1 mg to about 0.5 mg,about 0.5 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mgto about 2.0 mg, about 2.0 mg to about 2.5 mg, about 2.5 mg to about 3.0mg, about 3.0 mg to 4.0 mg, about 4.0 mg to about 5.0 mg, about 5.0 mgto about 7.0 mg, about 7.0 mg to about 9.0 mg, about 9.0 mg to about 15mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mgto about 35 mg, about 35 mg to about 45 mg, about 45 mg to about 60 mg,about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg toabout 90 mg, or about 90 mg to about 100 mg.

Silodosin

Silodosin has the chemical name2,3-dihydro-1-(3-hydroxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carboxamide and iscommercially available under the trademark RAPAFLO® in capsule form. Apharmaceutically acceptable salt of silodosin (e.g., silodosinhydrochloride) may be used. Silodosin may be administered via routesknown in the art, such as by oral administration. The amount ofsilodosin or a pharmaceutically acceptable salt thereof administered tothe patient can be in the range of, for example, about 0.1 mg to about50 mg per day. In certain embodiments, silodosin is administered (e.g.,orally) at a daily dosage ranging from about 0.1 mg to about 0.5 mg,about 0.5 mg to about 1.0 mg, about 1.0 mg to about 2.0 mg, about 2.0 mgto about 3.0 mg, about 3.0 mg to about 4.0 mg, about 4.0 mg to about 5.0mg, about 5.0 mg to about 6.0 mg, about 6.0 mg to about 7.0 mg, about7.0 mg to about 8.0 mg, about 8.0 mg to 10 mg, about 10 mg to about 15mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mgto about 35 mg, about 35 mg to about 45 mg, or about 45 mg to about 50mg. In certain other embodiments, silodosin is administered (e.g.,orally) at a daily dosage ranging from about 2.0 mg to about 6.0 mg,about 3.0 mg to about 5.0 mg, or about 3.5 mg to about 4.5 mg. In yetcertain other embodiments, silodosin is administered (e.g., orally) at adaily dosage ranging from about 6.0 mg to about 10 mg, about 7.0 mg toabout 9.0 mg, or about 7.5 mg to about 8.5 mg.

Tamsulosin

Tamsulosin has the chemical name5-[(2R)-2-[[2-(2-ethoxyphenoxyl)ethyl]amino]propyl]-2-methoxybenzenesulfonamide.A pharmaceutically acceptable salt of tamsulosin may be used. Forexample, the hydrochloride salt of tamsulosin is commercially availableunder the trademark FLOMAX® in capsule form. Tamsulosin may beadministered via routes known in the art, such as by oraladministration. The amount of tamsulosin or a pharmaceuticallyacceptable salt thereof administered to the patient can be in the rangeof, for example, about 0.05 mg to about 10 mg per day. In certainembodiments, tamsulosin is administered (e.g., orally) at a daily dosageranging from about 0.05 mg to about 0.10 mg, about 0.10 mg to about 0.20mg, about 0.20 mg to about 0.30 mg, about 0.30 mg to about 0.40 mg,about 0.40 mg to about 0.50 mg, about 0.50 mg to about 0.60 mg, about0.60 mg to about 0.70 mg, about 0.70 mg to about 0.80 mg, about 0.80 mgto about 0.90 mg, about 0.90 mg to about 1.0 mg, about 1.0 mg to about1.5 mg, about 1.5 mg to about 2.0 mg, about 2.0 mg to about 2.5 mg,about 2.5 mg to about 3.0 mg, about 3.0 mg to about 4.0 mg, about 4.0 mgto about 5.0 mg, about 5.0 mg to about 6.0 mg, about 6.0 mg to about 8.0mg, or about 8.0 mg to about 10 mg. In certain other embodiments,tamsulosin is administered (e.g., orally) at a daily dosage ranging fromabout 0.20 mg to about 0.60 mg, about 0.30 mg to about 0.50 mg, or about0.35 mg to about 0.45 mg. In yet certain other embodiments, tamsulosinis administered (e.g., orally) at a daily dosage ranging from about 0.60mg to about 1.0 mg, about 0.70 mg to about 0.90 mg, or about 0.75 mg toabout 0.85 mg.

Terazosin

Terazosin has the chemical name1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetrahydro-2-furanyl)carbonyl]piperazine.A pharmaceutically acceptable salt of terazosin (e.g., terazosinhydrochloride or terazosin hydrochloride dihydrate) may be used. Forexample, the hydrochloride salt of terazosin is commercially availableunder the trademark HYTRIN® in capsule form. Terazosin may beadministered via routes known in the art, such as by oraladministration. The amount of terazosin or a pharmaceutically acceptablesalt thereof administered to the patient can be in the range of, forexample, about 0.1 mg to about 50 mg per day. In certain embodimentsterazosin is administered (e.g., orally) at a daily dosage ranging fromabout 0.1 mg to about 0.5 mg, about 0.5 mg to about 1.0 mg, about 1.0 mgto about 1.5 mg, about 1.5 mg to about 2.0 mg, about 2.0 mg to about 2.5mg, about 2.5 mg to about 3.0 mg, about 3.0 mg to about 3.5 mg, about3.5 mg to about 4.0 mg, about 4.0 mg to about 4.5 mg, about 4.5 mg toabout 5.0 mg, about 5.0 mg to about 6.0 mg, about 6.0 mg to about 7.0mg, about 7.0 mg to about 8.0 mg, about 8.0 mg to about 9.0 mg, about9.0 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, or about40 mg to 50 mg. In certain other embodiments terazosin is administered(e.g., orally) at a daily dosage ranging from about 0.5 mg to about 1.5mg, about 0.8 mg to about 1.2 mg, or about 0.9 mg to about 1.1 mg. Incertain other embodiments, terazosin is administered (e.g., orally) at adaily dosage ranging from about 1.5 mg to about 2.5 mg, about 1.8 mg toabout 2.2 mg, or about 1.9 mg to about 2.1 mg.

Tolazoline

Tolazoline has the chemical name4,5-dihydro-2-(phenylmethyl)-1H-imidazole. A pharmaceutically acceptablesalt of tolazoline (e.g., tolazoline hydrochloride) may be used.Tolazoline may be administered via routes known in the art, such as byintravenous injection. The amount of tolazoline or a pharmaceuticallyacceptable salt thereof administered to the patient can be in the rangeof, for example, about 1 mg/kg body weight to about 100 mg/kg bodyweight per 24 hour period. In certain embodiments, tolazoline isadministered (e.g., intravenously) at a total daily dosage ranging fromabout 1 mg/kg body weight to about 2 mg/kg body weight, about 2 mg/kgbody weight to about 3 mg/kg body weight, about 3 mg/kg body weight toabout 5 mg/kg body weight, about 5 mg/kg body weight to about 7 mg/kgbody weight, about 7 mg/kg body weight to about 9 mg/kg body weight,about 9 mg/kg body weight to about 10 mg/kg body weight, about 10 mg/kgbody weight to about 20 mg/kg body weight, about 20 mg/kg body weight toabout 30 mg/kg body weight, about 30 mg/kg body weight to about 40 mg/kgbody weight, about 40 mg/kg body weight to about 60 mg/kg body weight,about 60 mg/kg body weight to about 80 mg/kg body weight, or about 80mg/kg body weight to about 100 mg/kg body weight.

Yohimbine

Yohimbine has the chemical name(16α,17α)-17-hydroxyyohimban-16-carboxylic acid methyl ester. Apharmaceutically acceptable salt of yohimbine (e.g., yohimbinehydrochloride) may be used. Yohimbine may be administered via routesknown in the art, such as by oral administration. The amount ofyohimbine or a pharmaceutically acceptable salt thereof administered tothe patient can be in the range of, for example, about 1 mg to about 50mg per day. In certain embodiments yohimbine is administered (e.g.,orally) at a daily dosage ranging from about 1.0 mg to about 2.0 mg,about 2.0 mg to about 3.0 mg, about 3.0 mg to about 4.0 mg, about 4.0 mgto about 5.0 mg, about 5.0 mg to about 6.0 mg, about 6.0 mg to about 7.0mg, about 7.0 mg to about 8.0 mg, about 8.0 mg to about 9.0 mg, about9.0 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45mg, or about 45 mg to about 50 mg.

Additional exemplary alpha-adrenergic receptor antagonists include, forexample, amosulalol, arotinolol, dapiprazole, ergoloid mesylates,fenspiride, indoramin, labetalol, naftopidil, nicergoline,phenoxybenzamine, phentolamine, typical and atypical antipsychotics,atipamezole, and pharmaceutically acceptable salts thereof.

It is appreciated that the alpha-adrenergic receptor antagonist may beadministered by traditional routes of administration known in the art.Certain routes of administration may be preferred for a particulartherapeutic agent, such as where a particular route of administrationreduces first-pass metabolism or has improved bioavailability. Incertain embodiments, the alpha-adrenergic receptor antagonist isadministered orally, transdermally, intradermally, or by transmucosaladministration alone or together in admixture with desmopressin. In yetother embodiments, the alpha-adrenergic receptor antagonist isadministered orally.

The method may also be characterized according to the time periodbetween the start of administration of desmopressin and administrationof the alpha-adrenergic receptor antagonist. In certain embodiments, thefirst administration of desmopressin may coincide with administration ofthe alpha-adrenergic receptor antagonist. Alternatively, the start ofadministration of desmopressin may be before or after the start ofadministration of the alpha-adrenergic receptor antagonist. In certainembodiments, the alpha-adrenergic receptor antagonist is administeredwithin 1 hour of the start of desmopressin administration. In certainembodiments, the alpha-adrenergic receptor antagonist is administeredwithin 0.5 hours, 1 hour, 1.5 hours, or 2 hours of the start ofdesmopressin administration.

Patient Populations

The methods are contemplated to provide a therapeutic benefit to humansubjects preferably adult males, suffering from disorders associatedwith or featuring undesirable voiding of a patient's bladder. Exemplarydisorders include nocturia, incontinence, enuresis, and diabetesinsipidus. In certain embodiments, the human subject suffers fromnocturia.

Restoration of Urine Production

The methods can be further characterized according to the time periodrequired in order for the subject to resume normal urine productionafter terminating administration of the desmopressin and 5-alphareductase inhibitor. It is important for the subject to resume normalurine production on a daily basis so that proper fluid balance ismaintained and waste can be excreted through urination. Accordingly, incertain embodiments, the method is further characterized in that urineproduction in the human subject is restored within about two hours afteradministration of desmopressin has been terminated. In certain otherembodiments, the method is further characterized in that urineproduction in the human subject is restored within about one hour afteradministration of desmopressin has been terminated.

Exemplary Benefits of the Combination Therapy

The methods and compositions are contemplated to provide variousbenefits. One contemplated benefit is improved efficacy in inhibitingthe urge to urinate in a human subject when desmopressin is administeredwith a 5-alpha reductase inhibitor compared to the efficacy observedwhen desmopressin is administered alone. In certain embodiments, theimprovement may be a 5%, 10%, 20%, 30%, 50%, 75%, 100%, or greaterimprovement in inhibiting the urge to urinate in a human subject whendesmopressin is administered with a 5-alpha reductase inhibitor comparedto the efficacy observed when desmopressin is administered alone.

Another contemplated benefit is a reduction in side effects associatedwith administration of desmopressin. In certain embodiments, thereduction in side effects may be a 5%, 10%, 20%, 30%, 50%, 75%, 100%, orgreater reduction in side effects in a human subject when desmopressinis administered with a 5-alpha reductase inhibitor compared to the sideeffects observed when desmopressin is administered alone at a dosagenecessary to achieve a similar therapeutic effect.

The administration of desmopressin and a 5-alpha reductase inhibitor mayresult in a synergistic effect, e.g., a synergistic improvement inefficacy in inhibiting the urge to urinate in a human subject. Incertain embodiments, the synergistic improvement in efficacy is at leasta 5%, 10%, 15%, 20%, 25%, 30%, or greater improvement in efficacycompared to the additive improvement in efficacy associated withadministration of desmopressin and a 5-alpha reductase inhibitortogether.

II. Pharmaceutical Compositions and Dosing Considerations

Another aspect of the invention provides a pharmaceutical compositioncomprising one or more therapeutic agents described herein and apharmaceutically acceptable carrier. The pharmaceutical compositions maybe specially formulated for administration in solid or liquid form,including those adapted for the following: (1) oral administration, forexample, drenches (aqueous or non-aqueous solutions or suspensions),tablets (e.g., those targeted for buccal, sublingual, and/or systemicabsorption), boluses, powders, granules, pastes for application to thetongue; (2) parenteral administration by, for example, subcutaneous,intramuscular, intravenous or epidural injection as, for example, asterile solution or suspension, or sustained-release formulation; (3)topical application, for example, as a cream, ointment, or acontrolled-release patch or spray applied to the skin; (4)intravaginally or intrarectally, for example, as a pessary, cream orfoam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.Further description of exemplary excipients and formulations designedfor a particular route of administration are described below.

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising desmopressin, a 5-alpha reductase inhibitor, anda pharmaceutically acceptable carrier. The 5-alpha reductase inhibitormay be, for example, dutasteride, epristeride, finasteride, izonsteride,turosteride, AS-601811, FK143, TF-505, or a pharmaceutically acceptablesalt thereof. In certain embodiments, the pharmaceutical composition isformulated for nasal administration to a human subject.

The phrase “pharmaceutically-acceptable carrier” means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, manufacturing aid (e.g.,lubricant, talc magnesium, calcium or zinc stearate, or steric acid), orsolvent encapsulating material, involved in carrying or transporting thesubject compound from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically-acceptable carriers include: (1) sugars, suchas lactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-shelled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient. The selected dosagelevel will depend upon a variety of factors including the activity ofthe particular compound of the present invention employed, or the saltthereof, the route of administration, the time of administration, therate of excretion or metabolism of the particular compound beingemployed, the rate and extent of absorption, the duration of thetreatment, other drugs, compounds and/or materials used in combinationwith the particular compound employed, the age, sex, weight, condition,general health and prior medical history of the patient being treated,and like factors well known in the medical arts.

A physician having ordinary skill in the art can readily determine andprescribe the effective amount of the pharmaceutical compositionrequired. For example, the physician could start doses of the compoundsof the invention employed in the pharmaceutical composition at levelslower than that required in order to achieve the desired therapeuticeffect and gradually increase the dosage until the desired effect isachieved.

III. Medical Kits

Another aspect of the invention provides a kit for inhibiting the urgeto urinate in a human subject or inducing an antidiuretic effect in ahuman subject. The kit comprises (i) instructions for use (ii)desmopressin and (iii) a 5-alpha reductase inhibitor, present in mixtureor separately, and if separate, administered differently, e.g., orallyfor the inhibitor and transmucosally or by way of a skin patch for thedesmopressin.

The description above describes multiple aspects and embodiments of theinvention, including therapeutic methods, pharmaceutical compositions,and medical kits. The patent application specifically contemplates allcombinations and permutations of the aspects and embodiments.

Aspects of the present disclosure can also be described as follows:

1. A method of inhibiting the urge to urinate in an adult human subjectover an interval of about two hours to no more than about eight hours,comprising administering to an adult human subject in need thereof aneffective, low dose amount of desmopressin and a 5-alpha reductaseinhibitor so that both exert physiological activity during anoverlapping time period.2. The method of 1, wherein the method inhibits the urge to urinate in ahuman subject over an interval of about four hours to about seven hours.3. The method of 1, wherein an antidiuretic effect is achieved over aninterval of about two hours to no more than about six hours.4. The method of 1, wherein an antidiuretic effect is achieved over aninterval of about four hours to no more than about seven hours.5. The method of any one of 1-4, wherein the administering achieves inthe subject a blood plasma concentration of desmopressin that does notexceed 15 pg/mL.6. The method of any one of 1-4, wherein the administering achieves inthe subject a blood plasma concentration of desmopressin that does notexceed 10 pg/mL.7. The method of any one of 1-4, wherein the administering achieves inthe subject a blood plasma concentration of desmopressin in the range ofabout 0.5 pg/mL to about 5 pg/mL.8. The method of any one of 1-4, wherein the administering achieves inthe human subject a blood plasma concentration of desmopressin in therange of about 0.5 pg/mL to about 2.5 pg/mL.9. The method of any one of 1-8, wherein desmopressin is administeredtransdermally, intradermally, or transmucosally across the oral or nasalmucosa.10. The method of any one of 1-8, wherein desmopressin is administeredtransdermally or intradermally.11. The method of any one of 1-8, wherein desmopressin is administeredintranasally.12. The method of any one of 1-8, wherein desmopressin is administeredsublingually across the oral mucosa.13. The method of 10, wherein desmopressin is administered at a fluxrate ranging from about 5 ng/hour to about 35 ng/hour.14. The method of 10, wherein desmopressin is administered at a fluxrate ranging from about 5 ng/hour to about 15 ng/hour.15. The method of any one of 1-14, wherein the 5-alpha reductaseinhibitor is dutasteride, epristeride, finasteride, izonsteride,turosteride, AS-601811, FK143, TF-505, or a pharmaceutically acceptablesalt thereof.16. The method of any one of 1-14, wherein the 5-alpha reductaseinhibitor is dutasteride.17. The method of any one of 1-14, wherein the 5-alpha reductaseinhibitor is finasteride.18. The method of any one of 1-14, wherein the 5-alpha reductaseinhibitor is a mixture of dutasteride and tamsulosin hydrochloride.19. The method of any one of 1-18, wherein the 5-alpha reductaseinhibitor is administered orally, transdermally, intradermally, oracross the nasal or oral mucosa.20. The method of any one of 1-18, wherein the 5-alpha reductaseinhibitor is administered orally.21. The method of any one of 1-20, wherein the 5-alpha reductaseinhibitor is administered within 1 hour before or after the start ofdesmopressin administration.22. The method of any one of 1-21, wherein the subject suffers fromnocturia, incontinence, enuresis, or diabetes insipidus.23. The method of any one of 1-21, wherein the subject suffers fromnocturia.24. The method of any one of 1-23, wherein urine production in the humansubject is restored within about two hours after administration ofdesmopressin has been terminated.25. The method of 1 comprising administering to the subject a 5-alphareductase inhibitor on a daily basis for a period of at least a monthand administering desmopressin before the subject retires to sleep.26. The method of 1 comprising administering to the subject a 5-alphareductase inhibitor at a dose level lower than its smallest drug labelrecommended dose for treatment of BPH and administering desmopressinbefore the subject retires to sleep.27. The method of 1 comprising administering to the subject as a mixturebefore the subject retires to sleep desmopressin and a 5-alpha reductaseinhibitor at a dose level lower than the smallest drug label recommendeddose of said inhibitor for treatment of BPH.28. The method of any one of 1-27, further comprising administering analpha-adrenergic receptor antagonist.29. The method of 28, wherein the alpha-adrenergic receptor antagonistis alfuzosin, amosulalol, arotinolol, dapiprazole, doxazosin, ergoloidmesylates, fenspiride, idazoxan, indoramin, labetalol, naftopidil,nicergoline, prazosin, silodosin, tamsulosin, terazosin, tolazoline,yohimbine, phenoxybenzamine, phentolamine, atipamezole, or apharmaceutically acceptable salt thereof.30. The method of any one of 1-29, wherein the subject is an adult, malehuman subject.31. A pharmaceutical composition comprising desmopressin, a 5-alphareductase inhibitor, and a pharmaceutically acceptable carrier.32. The pharmaceutical composition of 31, wherein the pharmaceuticalcomposition is formulated for intranasal or sublingual administration toa human subject.33. The pharmaceutical composition of 31 or 32, wherein the 5-alphareductase inhibitor is dutasteride, epristeride, finasteride,izonsteride, turosteride, AS-601811, FK143, TF-505, or apharmaceutically acceptable salt thereof.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1

A clinical study was performed to evaluate the impact of administeringdesmopressin in combination with a 5-alpha reductase inhibitor alone ortogether with an alpha-adrenergic receptor antagonist to reduce theoccurrence of nocturnal voiding by a patient. Experimental proceduresand results are described below. The results show that administration ofdesmopressin in combination with a 5-alpha reductase inhibitor alone ortogether with an alpha-adrenergic receptor antagonist results in agreater percentage of patients experiencing a reduction in theoccurrence of nocturnal voiding compared to administration ofdesmopressin alone, the 5-alpha reductase inhibitor alone, or the5-alpha reductase inhibitor together with an alpha-adrenergic receptorantagonist.

Part I—Experimental Procedures

Patients in the clinical study met the following criteria: (a) male orfemale that were at least 50 years old and experiencing on average atleast two nocturnal voids per night for a duration of at least sixmonths, and (b) do not suffer from any of congestive heart failure,diabetes insipidus, renal insufficiency, hepatic insufficiency,incontinence, illness requiring systemic steroids, malignancy within thepast 5 years, sleep apnea, nephrotic syndrome, unexplained pelvic mass,urinary bladder neurological dysfunction, have undergone urinary bladdersurgery or radiotherapy, or are pregnant or breast feeding.

Patients received as a nasal spray either (i) a 1.5 μg dosage ofdesmopressin or (ii) placebo. The desmopressin nasal spray (or placebo)was administered daily just prior to bedtime for a duration of twelveweeks. In addition, patients previously diagnosed as suffering frombenign prostatic hyperplasia (BPH) and receiving a 5-alpha reductaseinhibitor alone or together with an alpha-adrenergic receptor antagonistfor treatment of BPH continued to receive the 5-alpha reductaseinhibitor alone or together with the alpha-adrenergic receptorantagonist at the same dosage and frequency used prior to enrollment inthis study. All patients in this study who received a 5-alpha reductaseinhibitor alone or together with an alpha-adrenergic receptor antagonistfor treatment of their BPH had been receiving the 5-alpha reductaseinhibitor alone or together with the alpha-adrenergic receptorantagonist for at least 2 months before enrollment in this study andexperienced on average at least two nocturnal voids per night beforeenrollment in this study. The desmopressin nasal spray was prepared bycombining aliquots of an Emulsion Stock Solution and a Buffer Solutionas described below.

Emulsion Stock Solution:

To produce an emulsion stock solution, the following ingredients inparts by weight are added to a vessel equipped with a stirring bar, andmixed for 15 minutes at 60-65° C.: (i) 180 parts sorbitan monolaurate(Span-20) aqueous solution (12 mg/mL); (ii) 30 parts Polysorbate 20(Tween-20) aqueous solution (2 mg/mL); (iii) 400 parts cottonseed oilaqueous emulsion (26.6 mg/mL); (iv) 600 parts cyclopentadecanolide(CPE-215) aqueous emulsion (40 mg/mL); and (v) water to produce 1,500grams total batch size. After mixing, the preparation is homogenizedusing a high speed mixture at 6500 RPM+ for 20-25 minutes to produce afine emulsion. This solution is autoclaved to assure sterility.

Buffer Solution:

To produce a citric acid buffer stock solution, the followingingredients in parts by weight are added to a vessel equipped with astirring bar, and mixed for 5 minutes at 60-65° C.: (i) 6200 partswater; (ii) 16 parts anhydrous citric acid aqueous solution (1.85mg/mL); (iii) 76 parts sodium citrate, dihydrate aqueous solution (8.9mg/mL); (iv) 104 parts Polysorbate 20 (Tween-20) aqueous solution (12mg/mL); and (v) water to produce 8,500 grams total batch size.

Desmopressin Stock Solution:

To produce a desmopressin stock solution, 0.111 part desmopressinacetate trihydrate is added to sufficient buffer stock solution toproduce 100.0 mL of solution, and stirred until all the desmopressin isdissolved to produce a stock solution having a concentration of 100 μgdesmopressin/mL. From this stock solution a 30 μg/mL solution wasprepared by dilution.

Desmopressin Nasal Spray:

To produce the desmopressin nasal spray, aliquots of the 30 μg/mLsolution were filtered to eliminate any bacterial contamination anddiluted with an equal volume of emulsion stock solution to produceaseptic, preservative free dose forms comprising 15 μg/mL desmopressin,pH 5.5, containing 2% cyclopentadecanolide. These were bottled insterile pump spray bottles fitted with a Pfeiffer APF pump sprayers thatdeliver 100 μL per metered spray (i.e., 1.5 μg desmopressin (i.e., 1500ng desmopressin) per spray). The liquid contains no detectablemicroorganisms.

Patients recorded the occurrence of nocturnal voids during the studyperiod. Patients were designated to be a “Responder” if after receivingtreatment there was a reduction in the average number of nocturnal voidsduring the treatment period. Patients that did not experience areduction in the average number of nocturnal voids during the treatmentperiod were designated to be a “Non-Responder.”

Part II—Results

Results of the clinical study are shown in Tables 1-4 below. Table 1shows results of administering desmopressin or a placebo to BPH patientsreceiving an a 5-alpha reductase inhibitor alone or together with analpha-adrenergic receptor antagonist. The absolute response rate of BPHpatients treated with desmopressin in combination with a 5-alphareductase inhibitor alone or together with an alpha-adrenergic receptorantagonist was 57% compared to 17% for that group treated with placebo(i.e., no desmopressin). This is a difference of 40%.

TABLE 1 BPH PATIENTS RECEIVING DESMOPRESSIN COMBO THERAPY OR ONLY A5-ALPHA REDUCTASE INHIBITOR ALONE OR TOGETHER WITH AN ALPHA- ADRENERGICRECEPTOR ANTAGONIST Responder Patients Non-Responder Patients Number ofNumber of Number of Number of Second Patients Patients Patients Patients(or Third) that that that that Component of Received Received ReceivedReceived Combination Desmopressin Placebo Desmopressin Placebo Therapy(n = 14) (n = 12) (n = 14) (n = 12) 5-alpha 3  1* 4 5 reductaseinhibitor alpha- 5 1 2 5 adrenergic receptor antagonist and 5-alphareductase inhibitor Total Number 8 2 6 10  of Patients Percent Total 57%(8/14) 17% 43% (6/14) 83% (2/12) (10/12) *One patient was taking a5-alpha reductase inhibitor and an anticholinergic agent.

Table 2 shows results of administering desmopressin or a placebo topatients diagnosed with BPH, but which did not receive a 5-alphareductase inhibitor alone or together with an alpha-adrenergic receptorantagonist. The absolute response rate of BPH patients receivingdesmopressin (i.e., no alpha-adrenergic receptor antagonist or 5-alphareductase inhibitor) was 43% compared to 29% for that group on placebo(i.e., none of desmopressin, an alpha-adrenergic receptor antagonist, ora 5-alpha reductase inhibitor). This is a difference of 14%.

TABLE 2 BPH PATIENTS RECEIVING DESMOPRESSIN OR PLACEBO ResponderPatients Non-Responder Patients Number of Number of Second Number ofPatients Number of Patients (or Third) Patients that that Patients thatthat Component of Received Received Received Received CombinationDesmopressin Placebo Desmopressin Placebo Therapy (n = 42) (n = 56) (n =42) (n = 56) none 18 16 24 40 Percent Total 43% 29% 57% 71%

Table 3 shows results of administering desmopressin or a placebo to malepatients that did not have BPH and, therefore, were not receiving a5-alpha reductase inhibitor alone or together with an alpha-adrenergicreceptor antagonist. The absolute response rate of male patients withoutBPH receiving desmopressin was 53% compared to 35% for that group onplacebo (i.e., no desmopressin). This is a difference of 18%.

TABLE 3 MALE PATIENTS WITHOUT BPH THAT RECEIVED DESMOPRESSIN OR PLACEBOResponder Patients Non-Responder Patients Number of Number of SecondNumber of Patients Number of Patients (or Third) Patients that thatPatients that that Component of Received Received Received ReceivedCombination Desmopressin Placebo Desmopressin Placebo Therapy (n = 34)(n = 23) (n = 34) (n = 23) none 18 8 16 15 Percent Total 53% 35% 47% 65%

In sum, patients receiving the combination therapy (i.e., desmopressinin combination with a 5-alpha reductase inhibitor alone or together withan alpha-adrenergic receptor antagonist) had a higher absolute responserate and a higher relative response rate than patients receivingplacebo, compared to the response rates observed for (i) BPH patientsreceiving only desmopressin, and (ii) male patients without BPHreceiving only desmopressin. This is illustrated in Table 4 below.

TABLE 4 DATA ANALYSIS Difference in Absolute Responder Response ResponseRate Between Rate for Desmopressin- Patients treated Receiving Patients& Those Patient Population Desmopressin Receiving Placebo Responderpatients suffering from 57% 40% BPH and which received a 5-alphareductase inhibitor alone or together with an alpha-adrenergic receptorantagonist Responder patients suffering from 43% 14% BPH that did notreceive a 5-alpha reductase inhibitor or an alpha- adrenergic receptorantagonist Responder patients that were male 53% 18% and had not beendiagnosed with BPH and were not receiving a 5- alpha reductase inhibitoror an alpha-adrenergic receptor antagonist

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

We claim:
 1. A method of inhibiting in an adult human subject the urgeto urinate over an interval of about two hours to no more than abouteight hours while reducing the risk that the human subject developshyponatremia, comprising administering to an adult human subject in needthereof active agents consisting of an effective, low dose amount ofdesmopressin and a 5-alpha reductase inhibitor so that both exertphysiological activity during an overlapping time period, wherein whenthe 5-alpha reductase inhibitor is dutasteride or finasteride, the doseis lower than 0.5 mg/day for dutasteride and is lower than 5 mg/day forfinasteride.
 2. The method of claim 1, wherein the administeringachieves in the subject a blood plasma concentration of desmopres sinthat does not exceed 15 pg/mL.
 3. The method of claim 1, wherein theadministering achieves in the subject a blood plasma concentration ofdesmopres sin that does not exceed 10 pg/mL.
 4. The method of claim 1,wherein the administering achieves in the subject a blood plasmaconcentration of desmopressin in the range of about 0.5 pg/mL to about 5pg/mL.
 5. The method of claim 1, wherein the administering achieves inthe human subject a blood plasma concentration of desmopressin in therange of about 0.5 pg/mL to about 2.5 pg/mL.
 6. The method of claim 1,wherein desmopressin is administered transdermally, intradermally, ortransmucosally across the oral or nasal mucosa.
 7. The method of claim1, wherein desmopressin is administered transdermally or intradermally.8. The method of claim 1, wherein desmopressin is administeredintranasally.
 9. The method of claim 1, wherein desmopressin isadministered sublingually across the oral mucosa.
 10. The method ofclaim 7, wherein desmopressin is administered at a flux rate rangingfrom about 5 ng/hour to about 35 ng/hour.
 11. The method of claim 7,wherein desmopressin is administered at a flux rate ranging from about 5ng/hour to about 15 ng/hour.
 12. The method of claim 1, wherein the5-alpha reductase inhibitor is dutasteride, epristeride, finasteride,izonsteride, turosteride, AS-601811, FK143, TF-505, or apharmaceutically acceptable salt thereof.
 13. The method of claim 1,wherein the method inhibits in a human subject the urge to urinate overan interval of about four hours to about seven hours.
 14. The method ofclaim 1, wherein an antidiuretic effect is achieved over an interval ofabout two hours to no more than about six hours.
 15. The method of claim1, wherein an antidiuretic effect is achieved over an interval of aboutfour hours to no more than about seven hours.
 16. The method of claim 1,wherein when the 5-alpha reductase inhibitor is dutasteride, the dose is0.1 to 0.3 mg/day.
 17. The method of claim 1, wherein when the 5-alphareductase inhibitor is finasteride, the dose is less than 1.0 mg/day.